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Novel Pathways and Mechanism of Nicotine-Induced Oral Carcinogenesis

Sharma M, Shetty SS, Radhakrishnan R

Recent Pat Anticancer Drug Discov, 2021 08 06.
PMID: 34365933 DOI: 10.2174/1574892816666210806161312

BACKGROUND: Smokeless Tobacco (SLT) contains 9 times more nicotine than Smoked Tobacco (SMT). The carcinogenic effect of nicotine is intensified by converting nicotine-to-nicotine-derived Nitrosamines (NDNs).
METHODS: A review of the literature was conducted with a tailored search strategy to unravel the novel pathways and mechanisms of nicotine-induced oral carcinogenesis.
RESULTS: Nicotine and NDNs act on nicotinic Acetylcholine Receptors (nAChRs) as agonists. Nicotine facilitates cravings through α4β2nAChR and α7nAChR, via enhanced brain dopamine release. Nicotine binding to nAChR promotes proliferation, migration, invasion, chemoresistance, radioresistance, and metastasis of oral cancer cells. Nicotine binding to α7nAChR on keratinocytes triggers Ras/Raf-1/MEK1/ERK cascade promoting anti-apoptosis and pro-proliferative effects. Furthermore, the nicotine-enhanced metastasis is subdued on nAChR blockade through reduced nuclear localization of p-EGFR.
CONCLUSION: Protracted exposure to nicotine/NDN augments cancer-stimulatory α7nAChR and desensitizes cancer inhibitory α4β2nAChR. Since nAChRs dictate both addictive and carcinogenic effects of nicotine, it seems counterintuitive to designate nicotine just as an addictive agent devoid of any carcinogenicity.
Overexpression of S100A4 as a biomarker of metastasis and recurrence in oral squamous cell carcinoma

Natarajan J, Hunter K, Mutalik VS, Radhakrishnan R

J Appl Oral Sci, 2014 12 4;22(5):426-33.
PMID: 25466476

S100A4, a biomarker of epithelial mesenchymal transition (EMT), plays an important role in invasion and metastasis by promoting cancer cell motility. In oral squamous cell carcinoma (OSCC), metastasis results in 90% of cancer associated mortality.
OBJECTIVE: To investigate the role of S100A4 expression as an important component of the epithelial mesenchymal transition (EMT) program in oral squamous cell carcinoma (OSCC).
MATERIAL AND METHODS: S100A4 protein expression was assessed semi-quantitatively by immunohistochemistry in 47 histologically confirmed cases of oral squamous cell carcinoma (OSCC) and 10 normal oral mucosal biopsies. The association between the S100A4 overexpression and the aggressive features of OSCC were analyzed by X2 test.
RESULTS: Moderate to strong cytoplasmic expression of S100A4 was observed in 30 out of 47 specimens of OSCC (64%). Overexpression of S100A4 was significantly associated with the clinical stage, lymph node involvement, metastases, pattern of invasion and recurrence (p<0.05).
CONCLUSION: S100A4 expression represents an important biomarker of prognostic significance that may be used to identify a subset of patients at high risk of invasion and metast.
Clear cell variant of calcifying epithelial odontogenic tumor without calcification: a rarity

Mutalik VS, Nichat P, Carnelio S, Solomon M, Radhakrishnan R

J Contemp Dent Pract, 2014 Jan 1;15(1):119-21.
PMID: 24939279

Calcifying epithelial odontogenic tumor (CEOT) is a rare, benign, locally aggressive odontogenic epithelial tumor that affects the jaws. Although there are numerous reports on the variants of CEOT, occurrence of clear cells with complete absence of calcification has been a rarity. Histochemical analysis of tumor cells revealed glycogen granules with PAS staining, with absence of CD 1a staining in clear cells, while the amyloid-like deposit associated with clear cells showed green birefringence with Congo red. We report an unusual variant of CEOT occurring in a 27 years old male patient.
Fulltext Signaling pathways promoting epithelial mesenchymal transition in oral submucous fibrosis and oral squamous cell carcinoma

Shetty SS, Sharma M, Fonseca FP, Jayaram P, Tanwar AS, Kabekkodu SP, et al.

Jpn Dent Sci Rev, 2020 Nov;56(1):97-108.
PMID: 32874377 DOI: 10.1016/j.jdsr.2020.07.002

Epithelial-mesenchymal transition (EMT) is a critical process that occurs during the embryonic development, wound healing, organ fibrosis and the onset of malignancy. Emerging evidence suggests that the EMT is involved in the invasion and metastasis of cancers. The inflammatory reaction antecedent to fibrosis in the onset of oral submucous fibrosis (OSF) and the role of EMT in its malignant transformation indicates a hitherto unexplored involvement of EMT. This review focuses on the role of EMT markers which are regulators of the EMT mediated complex network of molecular mechanisms involved in the pathogenesis of OSF and OSCC. Further the gene enrichment analysis and pathway analysis supports the association of the upregulated and downregulated genes in various EMT regulating pathways.
Role of Yes-associated protein and transcriptional coactivator with PDZ-binding motif in the malignant transformation of oral submucous fibrosis

Sharma M, Hunter KD, Fonseca FP, Shetty SS, Radhakrishnan R

Arch Oral Biol, 2021 Aug;128:105164.
PMID: 34044344 DOI: 10.1016/j.archoralbio.2021.105164

OBJECTIVE(S): The objective of the present manuscript is to elucidate the role of matrix stiffness in the malignant transformation of oral submucous fibrosis.
DESIGN: The role of matrix stiffness in several cancers including oral cancer was reviewed with a tailored search strategy using relevant keywords as per the Medline format. The role of molecular mediators, Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) was weighed in the context of OSF along two distinct pathways.
RESULTS: Increased matrix stiffness activates the transcriptional coactivators, YAP and TAZ shuttling between the nucleus and cytoplasm. YAP and TAZ, serve as mechanical transducers in promoting cell migration, invasion and epithelial-mesenchymal transition (EMT). The hypoxic microenvironment in the advanced stage of OSF promotes the migratory phenotype through mechanical memory.
CONCLUSIONS: Reprogramming of a stiff matrix has the potential to restore the Hippo-YAP/TAZ tumor suppressor pathway and reverse fibrosis-associated tumor development.
Fulltext Understanding the molecular mechanism associated with reversal of oral submucous fibrosis targeting hydroxylysine aldehyde-derived collagen cross-links

Shetty SS, Sharma M, Kabekkodu SP, Kumar NA, Satyamoorthy K, Radhakrishnan R

J Carcinog, 2021;20:9.
PMID: 34526855 DOI: 10.4103/jcar.JCar_24_20

Fibrosis is a pathological state characterized by excessive deposition of the extracellular matrix components leading to impaired tissue function in the affected organ. It results in scarring of the affected tissue akin to an over-healing wound as a consequence of chronic inflammation and repair in response to injury. Persistent trauma of susceptible oral mucosa due to habitual chewing of betel quid resulting in zealous healing of the mucosal tissue is one plausible explanation for the onset of oral submucous fibrosis (OSF). The irreversibility and resistance of collagen to degradation and its high potential to undergo malignant change are a major reason for morbidity in OSF. Hence, early diagnosis and timely treatment are crucial to prevent the progression of OSF to malignancy. This review focuses on the mechanistic insight into the role of collagen cross-links in advancing fibrosis and possible therapeutic targets that bring about a reversal of fibrosis. These options may be beneficial if attempted as a specific therapeutic modality in OSF as is in organ fibrosis. The upregulation of lysyl oxidase and lysyl hydroxylase has been shown to exhibit the higher levels of the hydroxylysine aldehyde-derived cross-links in fibrosis and tumor stroma promoting the tumor cell survival, resistance, and invasion. The in silico analysis highlights the potential drugs that may target the genes regulating collagen crosslinking.
Biological implications of the immune factors in the tumour microenvironment of oral cancer

Shetty SS, Padam KSR, Hunter KD, Kudva A, Radhakrishnan R

Arch Oral Biol, 2021 Oct 24;133:105294.
PMID: 34735925 DOI: 10.1016/j.archoralbio.2021.105294

OBJECTIVE: The objective of this review is to decipher the biological implications of the immune factors in the tumour microenvironment in oral cancer. The restoration of balance between tumour tolerance and tumour eradication by the host immune cells is critical to provide effective therapeutic strategies.
DESIGN: The specific role of the stromal and the immune components in oral cancer was reviewed with a tailored search strategy using relevant keywords. The articles were retrieved from bibliometric databases indexed in PubMed, Scopus, and Embase. An in silico analysis was performed to identify potential drug candidates for immunotherapy, by accessing the Drug-Gene Interactions Database (DGIdb) using the rDGIdb package.
RESULTS: There is compelling evidence for the role of the cellular and extracellular components of the tumour microenvironment in inducing immunosuppression and progression of oral cancer. The druggable candidates specifically targeting the immune system are a viable option in the treatment of oral cancer as they can regulate the tumour microenvironment.
CONCLUSION: A complex interaction between the tumour and the immunological microenvironment influences the disease outcome in oral cancer. Targeting specific components of the immune system might be relevant, as immunotherapy may become the new standard of care for oral cancer.
Bell Palsy: Facts and Current Research Perspectives

Rajangam J, Lakshmanan AP, Rao KU, Jayashree D, Radhakrishnan R, Roshitha B, et al.

CNS Neurol Disord Drug Targets, 2024;23(2):203-214.
PMID: 36959147 DOI: 10.2174/1871527322666230321120618

Bell palsy is a non-progressive neurological condition characterized by the acute onset of ipsilateral seventh cranial nerve paralysis. People who suffer from this type of facial paralysis develop a droop on one side of their face, or sometimes both. This condition is distinguished by a sudden onset of facial paralysis accompanied by clinical features such as mild fever, postauricular pain, dysgeusia, hyperacusis, facial changes, and drooling or dry eyes. Epidemiological evidence suggests that 15 to 23 people per 100,000 are affected each year, with a recurrence rate of 12%. It could be caused by ischaemic compression of the seventh cranial nerve, which could be caused by viral inflammation. Pregnant women, people with diabetes, and people with respiratory infections are more likely to have facial paralysis than the general population. Immune, viral, and ischemic pathways are all thought to play a role in the development of Bell paralysis, but the exact cause is unknown. However, there is evidence that Bell's hereditary proclivity to cause paralysis is a public health issue that has a greater impact on patients and their families. Delay or untreated Bell paralysis may contribute to an increased risk of facial impairment, as well as a negative impact on the patient's quality of life. For management, antiviral agents such as acyclovir and valacyclovir, and steroid treatment are recommended. Thus, early diagnosis accompanied by treatment of the uncertain etiology of the disorder is crucial. This paper reviews mechanistic approaches, and emerging medical perspectives on recent developments that encounter Bell palsy disorder.